The primary objective of this project is to develop new drugs effective in the treatment of various hyperlipoproteinemic conditions and atherosclerosis. To accomplish this goal we are currently studying the synthesis and biological properties of a number of compounds related to clofibrate (ethyl 2-(4-chlorophenoxy-2-methylpropionate). We plan to study (and in many cases are presently studying) appropriately constructed analogs for their selective activity in a variety of biological systems in vivo and in vitro for purposes of (a) defining minimum structural requirements for maximum as well as differential antilipemic properties, (b) determining their effect on lipoprotein patterns in experimental animals, (c) correlating physicochemical properties with biological activity, (d) probing into the nature of receptors which are either blocked or stimulated by clofibrate and classifying such sites according to their selective affinity and/or intrinsic activity towards various racemic and optically pure enantiomorphs, (e) determining their effects on enzyme induction and cholesterol catabolism and excretion, (f) elucidating their mechanism(s) of actions in vivo and in vitro, and (g) studying the effect of structural modification on absorption, distribution and metabolism. The results of these studies will provide directions for future synthetic work and ultimately should lead to the accomplishment of our primary objective. In order to carry out this work we will synthesize optically active and radiolabeled analogs of compounds which have promising biological properties as assessed in Triton-induced hyperlipemic rats and other animal models in vivo. Biological data in vivo and in vitro will be analyzed in light of the physicochemical properties (stability (hydrolytic), pKa, solubility, partition coefficients, etc.) of new and old analogs. BIBLIOGRAPHIC REFERENCES: W.S. Mellon, D.T. Witiak, and D.R. Feller. The interrelationship between hepatic microsomal cholesterol 7alpha-hydroxylase and mixed function oxidase (MFO) systems, The Pharmacologist, 18, 155, (1976).